Breast cancer is the highest incident cancer for Japanese females. Breast cancer often depends on hormone (estrogen: E2). Proliferation of breast cancer is promoted through activation of a receptor of the hormone (estrogen receptor: ER). As a mechanism for breast cancer proliferation by ER activation, two different mechanisms are reported: a mechanism in which ER functions as a transcriptional regulator (genomic activation); and a mechanism in which ER participates in the activation of intracellular phosphorylation cascade as a membrane-type ER localized on a cell membrane (non-genomic activation) (Non-Patent Documents 1 to 3). However, there are still many unclear points for the molecular mechanism of the ER activation itself.
In addition, the survival rate of breast cancer patients is remarkably improved by using tamoxifen (TAM) as an antiestrogen in postoperative adjuvant therapy or in standard treatment of advanced or relapsed breast cancer. However, about 30% of ER-positive breast cancer is refractory to TAM. In addition, according to a standard treatment, TAM is administered for 5 years in a postoperative adjuvant therapy. Thus, there is a serious problem in that prolonged use of TAM makes breast cancer cells resistant to TAM (Non-Patent Documents 1 to 3). As a mechanism of this TAM-refractoriness or resistance, there are several mechanisms reported such as accelerated estrogen sensitiveness, and crosstalk of a membrane receptor such as EGER, HER2 and IGFR with a signal route of a growth factor (Non-Patent Documents 1 to 3). However, there are still many unclear points about the mechanism of refractory or resistance to TAM. In addition, in recent years, aromatase inhibitors or LH-RH agonist preparations are also used in treatment for breast cancer. However, these medicines suppress estrogen production. Thus, side effects are reported, such as a decrease in bone density due to a decrease in estrogen level. As described above, urgent problems are elucidation of the ER activity-regulated mechanism of the E2-dependent breast cancer and development of a novel therapeutic agent TIN the E2-dependent breast cancer.
The present inventors have identified so far to novel Estrogen Receptor Activity-regulated Protein 1 (ERAP1) (also known as BIG3) observed to be highly expressed specifically in breast cancer at high frequency, through a comprehensive analysis of gene expression in breast cancer using cDNA microarray (Patent Document 1 and Non-Patent Document 4). The findings as described below are obtained by a detailed analysis of functions of ERAP1. Namely ERAP1 binds to PHB2/REA protein (prohibition 2/Repressor of Estrogen Activity), a repressor of ER activation in the cytoplasm, to block E2-dependent nuclear translocation of PHB2/REA. Therefore, ERAP1 may lead to constitutive activation of ER in breast cancer cells by inhibiting ERα activity-suppression function of PFB2/REA (Patent Document 1 and Non-Patent Document 4).